Are developing β-adrenoceptors able to desensitize? Acute and chronic effects of β-agonists in neonatal heart and liver

Abstract

During fetal and neonatal development, β-adrenergic receptors (β-ARs) appear to be resistant to desensitization by β-agonist drugs. To determine the mechanisms underlying the regulatory differences between adults and neonates, we administered isoproterenol, a mixed β1/β2-AR agonist, and terbutaline, a β2-selective agonist. Effects were examined in the ensuing 4 h after a single injection, or after the last of four daily injections. We prepared cell membranes from heart (predominantly β1-ARs) and liver (predominantly β2-ARs) and assessed signal transduction in the adenylyl cyclase (AC) pathway. In the first few hours after a single administration of isoproterenol to adult rats, cardiac β-ARs showed activation of G proteins (elevated AC response to forskolin) and desensitization of β-AR-mediated responses; after the fourth injection, heterologous desensitization emerged, characterized by a loss of signaling mediated either through β-ARs or glucagon receptors. Terbutaline evoked an increase in the forskolin response but no desensitization of receptor-mediated responses. When we gave the same treatments to neonatal rats, we observed cardiac G protein activation, but there was neither homologous nor heterologous desensitization of β-ARs or glucagon receptors. In the adult liver, isoproterenol and terbutaline both failed to evoke desensitization, regardless of whether the drugs were given once or for 4 days. In neonates, however, acute or chronic treatment elicited homologous desensitization of β-AR-mediated AC signaling, while sensitizing the response to glucagon. These results show that neonatal β-ARs are inherently capable of desensitization in some, but not all, cell types; cellular responses can be maintained through heterologous sensitization of signaling proteins downstream from the receptor. Differences from adult patterns of response are highly tissue selective and are likely to depend on ontogenetic differences in subtypes of β-ARs and AC.

Hypotension in the chronically hypoxic chicken embryo is related to the β-adrenergic response of chorioallantoic and femoral arteries and not to bradycardia

“…Differentiated, tissue-specific ␤AR regulation has previously been demonstrated and ascribed to receptor concentration, receptor subtype ratio, adenylyl cyclase isoform expression, and G protein expression (4). With our present data, we cannot discriminate which of the above factors is responsible for the increased ␤AR-mediated relaxation.…”

“…Although high levels of circulating catecholamines are known to desensitize and downregulate ␤-adrenergic receptors in adult cardiac tissue, we and others have previously shown that embryonic hypoxia sensitizes ␤ARs rather than desensitizes them. The stimulatory effect of catecholamines on the heart is thereby maintained (4,24).…”

Ontogeny of phosphoinositide 3-kinase signaling in developing heart: effect of acute β-adrenergic stimulation

“…The same dosing regimen has been used by us and other investigators. For example, Auman et al (3) showed that the same dosing regimen for Iso activates basal adenylyl cyclase activities, measured 1-4 h after treatment, in neonatal and adult hearts. There is no homologous or heterologous desensitization of ␤-AR-mediated responses in neonatal heart and only a slight but not significant increase in homologous desensitization 1 h after Iso injection in adult hearts.…”

“…The levels of PTEN were, however, not affected by the same treatment, suggesting a direct action of acute ␤-AR stimulation on PI3K signaling in postnatal hearts. During development, ␤-AR stimulation-induced receptor desensitization or downregulation is not present until 2 wk of age (3,44). The absence of ␤-AR desensitization in early development may be physiologically critical, as ␤-AR signaling is required for maintaining proper homeostasis and growth of the heart.…”

β-Adrenoceptor signaling in regenerating skeletal muscle after β-agonist administration

“…Experiments using heart, lung, brown fat, and liver suggest that immature, developing tissue is resistant to desensitization by chronic ␤-agonist exposure (3,4,9,29,36). These observations indicate that the downregulation and desensitization responses may not be inherent but are acquired during development.…”